title: Antisense oligonucleotide inhibition of cholesteryl ester transfer protein enhances RCT in hyperlipidemic, CETP transgenic, LDLr-/- mice.
abstract: Due to their ability to promote positive effects across all of the lipoprotein classes, cholesteryl ester transfer protein (CETP) inhibitors are currently being developed as therapeutic agents for cardiovascular disease. In these studies, we compared an antisense oligonucleotide (ASO) inhibitor of CETP to the CETP small molecule inhibitor anacetrapib. In hyperlipidemic CETP transgenic (tg) mice, both drugs provided comparable reductions in total plasma cholesterol, decreases in CETP activity, and increases in HDL cholesterol. However, only mice treated with the antisense inhibitor showed an enhanced effect on macrophage reverse cholesterol transport, presumably due to differences in HDL apolipoprotein composition and decreases in plasma triglyceride. Additionally, the ASO-mediated reductions in CETP mRNA were associated with less accumulation of aortic cholesterol. These preliminary findings suggest that CETP ASOs may represent an alternative means to inhibit that target and to support their continued development as a treatment for cardiovascular disease in man.
authors.affiliation: Cardiovascular Antisense Drug Discovery Group, Isis Pharmaceuticals, Inc., Carlsbad, CA 92010.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Bell
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Graham
authors.forename: Richard G
authors.initials: RG
authors.lastname: Lee
authors.forename: Adam E
authors.initials: AE
authors.lastname: Mullick
authors.forename: Wuxia
authors.initials: W
authors.lastname: Fu
authors.forename: Dan
authors.initials: D
authors.lastname: Norris
authors.forename: Rosanne M
authors.initials: RM
authors.lastname: Crooke
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001011:Aorta / Q000378:metabolism; D001692:Biological Transport; D002318:Cardiovascular Diseases / Q000209:etiology / Q000517:prevention & control; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood; D003131:Combined Modality Therapy; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006949:Hyperlipidemias / Q000097:blood / Q000150:complications / Q000628:therapy*; D008077:Lipoproteins, LDL / Q000097:blood; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016376:Oligonucleotides, Antisense / Q000235:genetics*; D023303:Oxazolidinones / Q000494:pharmacology / Q000627:therapeutic use; D034622:RNA Interference; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D014280:Triglycerides / Q000097:blood / Q000378:metabolism
chemical_list: D000924:Anticholesteremic Agents; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D008077:Lipoproteins, LDL; D016376:Oligonucleotides, Antisense; D023303:Oxazolidinones; D011973:Receptors, LDL; D014280:Triglycerides; C530884:anacetrapib
keywords: cardiovascular disease; cholesteryl ester transfer protein; lipoprotein metabolism; low density lipoprotein